It is clear that repeated exposure to stress increases the risk of developing and expressing symptoms of human disorders of fear and anxiety;however, little is known about the mechanisms by which this occurs. Many studies have shown that numerous brain areas, including the hippocampus, are adversely impacted by chronic stress. For example, chronic stress has been directly linked to atrophy of neuronal processes, reduction of neural plasticity, and deficits in behavioral performance on mnemonic tasks. However, recent data indicates that one brain region, the amygdala, exhibits a relatively unique response to chronic stress. That is, chronic stress causes growth of dendritic processes in amygdala neurons and increases in anxiety. These findings suggest the intriguing hypothesis that chronic stress produces fundamentally opposing effects in the hippocampus and amygdala. We have behavioral data supporting this hypothesis: Chronic stress enhances amygdala-dependent delay fear conditioning but impairs hippocampus-dependent trace fear conditioning. In this proposal, we will combine sophisticated multi-site tetrode recording techniques and cutting-edge molecular methods (viral-mediated gene transfer) with immunohistochemical and behavioral techniques in rats to further examine this hypothesis and explore two mechanisms by which opposing effects may occur. First, we will characterize chronic stress-induced changes in both spontaneous and associative spike firing in the hippocampus and amygdala. Second, we will determine whether glucocorticoids, making up one component of the neuroendocrine response to stress, produce opposing effects on electrophysiological, behavioral, and gene expression measures in the amygdala and hippocampus. Third, we will determine the contribution of growth hormone, a gene that is oppositely regulated in the hippocampus and amygdala after chronic stress, to stress- induced changes in behavioral measures of fear memory. Because of the important role that the amygdala plays in regulating anxiety and fear, experiments assessing the unique effects of chronic stress on the amygdala may shed light on the specific mechanisms by which chronic stress exacerbates mental illnesses such as post-traumatic stress disorder. Identifying mechanisms by which stress exacerbates fear may lead to new therapeutic targets for the treatment of mental illness. PUBLIC HEALTH RELEVANCE: This research will compare the impact of chronic and intense stress on the hippocampus and amygdala and determine the contribution of glucocorticoids (a hormone secreted in response to stress) and growth hormone (a hormone that is uniquely upregulated in the amygdala after chronic stress) to these effects. This work will shed light on the multiple ways in which chronic stress can enhance fear and anxiety, and it will identify novel therapeutic strategies by which stress-enhancement of fear memory may be reduced. This is particularly important as chronic stress is a potent trigger for affective mental illnesses such as post-traumatic stress disorder (PTSD), but the mechanisms by which stress triggers this class of mental illnesses is unknown.